Synthesis of thienamycin via (3SR, 4RS)-3-[1 (SR)-hydroxyethyl]-2-oxo-4-azetidineacetic acid

ABSTRACT

Disclosed is a process for the stereocontrolled total synthesis of thienamycin via intermediates II and IIa:    &lt;IMAGE&gt;  II   &lt;IMAGE&gt; IIa  wherein R is a readily removable carboxyl protecting group.

This is a division of application Ser. No. 252,103 filed Apr. 8, 1981,now U.S. Pat. No. 4,349,687 which is a continuation of U.S. Ser. No.112,021 filed Jan. 14, 1980, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a stereocontrolled total synthesis of theknown antibiotic thienamycin (I). ##STR1## Starting from acetonedicarboxylate, the synthesis proceeds in a stereo-selective way viaintermediates II and IIa: ##STR2## wherein R¹ is a readily removableprotecting group such as benzyl, β,β,β-trichloroethyl, methyl, ethyl,phenyl, t-butyl and the like.

DETAILED DESCRIPTION OF THE INVENTION

The process of the present invention may conveniently be summarized bythe following reaction diagram: ##STR3##

In words relative to the above reaction diagram, the acetonedicarboxylate starting material 1 (R¹ is alkyl having from 1-6 carbonatoms, aryl, such as phenyl, or aralkyl having from 7-12 carbon atoms)in a solvent such as toluene, methylene chloride, ethyl acetate, etheror the like is treated with an amine, NH₂ R (R is hydrogen; phenylalkylhaving from 7-12 carbon atoms such as benzyl; 2,4-dimethoxybenzyl; alkylhaving from 1-6 carbon atoms such as t-butyl; or an amine, such asα-methylbenzylamine, or the like) at a temperature of from -10° to 110°C., for from 0.5 to 24 hours. The above reaction mixture for thetransformation 1→2 is conducted in the presence of a dehydrating agentsuch as sodium sulfate, molecular sieves, or the like.

The transformation 2→3 is accomplished by treating 2 in a solvent suchas toluene, methylene chloride, ethyl acetate, ether or the like with astoichiometric to 100-fold excess of ketene, acetic anhydride, or acetylhalide such as acetyl chloride in the presence of a base such as atriorganoamine, for example, triethylamine, at a temperature of from-10° to 95° C. for from 10 minutes to 15 hours.

The transformation 3→4 is accomplished by treating 3 in a solvent suchas acetic acid, ethanol, methanol or the like at a temperature of from0° to 80° C. with a reducing agent such as sodium cyanoborohydride,sodium borohydride, sodium acetoxyborohydride, or the like, in thepresence of a carboxylic acid such as acetic, tartaric, oxalic or thelike.

Cyclization of 4 to form the lactone 5 is accomplished by treating 4 ina solvent such as methylene chloride, ether, toluene, water, or the likewith an acid such as hydrochloric, sulfuric, phosphoric,trifluoroacetic, or the like at a temperature of from 0° to 100° forfrom 0.5 to 20 hours. Cyclization of 4 to form 5, wherein R¹ ishydrogen, is accomplished by heating a solution of 4 in concentratedaqueous HCl or equivalent acid, at from 25° to 100° C. for from 2 to 12hours. It should be noted that these latter conditions will also convert5 (R¹ =protecting group) to 5 (R¹ =hydrogen).

The deblocking transformation 5→5a is typically achieved by catalytichydrogenation in a solvent such as acetic acid, water, or the like undera hydrogenation pressure of from 40-1500 psi in the presence of ahydrogenation catalyst such as palladium on charcoal, palladiumhydroxide, platinum oxide or the like.

The transformation 5a→5b is accomplished by treating 5a with an alcoholsuch as benzyl alcohol, 2,2,2-trichloroethanol, methanol, phenol or thelike at a temperature of from 25°-100° C. for from 1 to 24 hours. Thevalue of R¹ is determined by the alcohol R¹ OH utilized in thetransformation 5a→5b. Suitable values for R¹ have generically beendefined above relative to starting material 1.

It should be noted that intermediate 5a is racemic. Resolution at thisstage to the desired 2S,3S,4R-isomer affords optically pure thienamycinon completion of the synthesis. Resolution of 5a (or its protectedintermediate 5) is conveniently accomplished by crystallization with anoptically active acid. The preferred means of resolution is accomplishedon crystallization with camphorsulfonic acid, (-) or (+)phenethylsulfonic acid and (-) or (+)α-methoxy-α-trifluoromethylphenylacetic acid, or the like. Suchresolution is described and claimed in concurrently filed, commonlyassigned U.S. patent application Ser. No. 112,020, filed Nov. 4, 1980[Merck & Co., Inc., of George Gal, et al.]; this application isincorporated herein by reference to the extent that it describes theresolution of 5a.

The transformation 5b→5c is accomplished by treating 5b withdicyclohexylcarbodiimide (DCC), or the like in the presence of a basesuch as triethylamine, 4-dimethylaminopyridine, pyridine, or the like.

The oxidation 5c→5d is accomplished with an oxidizing agent such asJones reagent, dipyridine chromium (VI) oxide, trifluoroaceticanhydride-dimethylsulfoxide-triethylamine, pyridinium dichromate, aceticanhydride-dimethylsulfoxide-triethylamine in a solvent such as methylenechloride, acetonitrile, or the like at a temperature of from -78° to 25°C. for from 5 minutes to 5 hours.

The reduction 5d→6 is accomplished by treating the ketone with areducing agent such as sodium cyanoborohydride, potassiumtri(sec-butyl)borohydride, lithium tri(sec-butyl)borohydride, sodiumborohydride, lithium aluminum hydride or the like in a solvent such asdiethylether, tetrahydrofuran, toluene or the like at a temperature offrom -20° to 25° C. The reaction can conveniently be conducted in thepresence of an added complexing salt such as potassium iodide, magnesiumbromide or the like.

Establishment of protecting group R² is accomplished by thetransformation 6→7. Preferably 6 in a solvent such as dimethylformamide,ethyl acetate, methylene chloride, or the like is reacted with a reagentcapable of establishing R². Preferred protecting groups aretriorganosilyls such as tert-butyldimethylsilyl, or the like. Typically,protecting groups R² are established by treating 6 in a solvent such asdimethylformamide, ethylacetate, methylene chloride, or the like in thepresence of a base such as pyridine, triethylamine, or the like with astoichiometric to 4-fold excess of tert-butyldimethylsilyl chloride at atemperature of from 25° to 70° C. for from 3 to 48 hours.

It should be noted that establishment of protecting group R² isoptional; the chain elongation reaction 8→9 can efficiently beaccomplished when R² =hydrogen.

The deblocking of the carboxyl group is accomplished in thetransformation 7→8. Typically the deprotection is accomplished bycatalytic hydrogenation. Typically, 7 and the solvent such as methanol,ethylacetate, ether, or the like under a hydrogen pressure of from 1 to3 atmospheres in the presence of a hydrogenation catalyst such aspalladium on charcoal, platinum oxide, or the like is held at atemperature of from 0° to 40° C. for from 1 to 3 hours, to provide 8.Other deblocking procedures, such as hydrolysis, are also appropriate.Thus, for example, when R¹ is methyl, basic hydrolysis is preferred:Typically, this is accomplished by the addition of an equivalent amountof a base such as NaOH, KOH, Ba(OH)₂, Na₂ CO₃, or the like to an aqueoussolution of 7 (for example, as the methyl ester) at 25°-100° C. for from1.0 min. to 10 hours.

The addition 8→9 is accomplished by treating 8 with1,1'-carbonyldimidazole or the like in a solvent such astetrahydrofuran, dimethoxyethyane, or the like at a temperature of from0° to 50° C., followed by the addition of 1.1 to 3.0 equivalents of (R³O₂ CCH₂ CO₂)₂ Mg, or the like at a temperature of from 0° to 50° C. forfrom 1 to 48 hours. R³ is a readily removable carboxyl protecting groupsuch as p-nitrobenzyl, o-nitrobenzyl, benzyl or the like.

The removal of the protecting groups R² is accomplished by treating 9 ina solvent such as 10% aqueous methanol, tetrahydrofuran, or the like inthe presence of hydrochloric acid, sulfuric acid, phosphoric acid, orthe like at a temperature of 0° to 50° C. for from 10 minutes to 10hours to provide intermediate 10.

The diazotization reaction 10→11 is accomplished by treating 10 in asolvent such as ethyl acetate, methylene chloride, toluene, or the like,with a diazotization reagent such as p-toluenesulfonyl azide,p-carboxybenzenesulfonyl azide or the like in the presence of a basesuch as pyridine, triethylamine, or the like at a temperature of from 0°to 40° C. for from 10 to 120 minutes.

Cyclization (11→12) is accomplished by treating 11 in a solvent such asbenzene, toluene, THF or the like at a temperature of from 50°-110° C.for from 1-5 hours in the presence of a catalyst such as bis(acetylacetonato) Cu (II) [Cu(acac)₂ ], CuSO₄, Cu powder, Rh₂ (OAc)₄, orPd(OAc)₂. Alternatively, the cyclization may be accomplished byirradiating 11 through a pyrex filter (a wave length greater than 300nm) in a solvent such as benzene, CCl₄, diethylether or the like at atemperature of from 0°-25° C. for from 0.5 to 2 hours. ["OAc"=acetate].

Establishment of leaving group X (12→13) is accomplished by reacting theketo ester 12 with R°X such as p-toluenesulfonic acid anhydride,p-nitrophenylsulfonic acid anhydride, 2,4,6-triisopropylphenylsulfonicacid anhydride, methanesulfonic acid anhydride, toluenesulfonylchloride, p-bromophenylsulfonyl chloride, or the like; wherein: X is thecorresponding leaving group such as toluene sulfonyloxy,p-nitrophenylsulfonyloxy, methanesulfonyloxy, p-bromophenylsulfonyloxy;or other leaving groups which are established by conventional proceduresand are well known in the art. Typically, the above reaction toestablish leaving groups X is conducted in a solvent such as methylenechloride, acetonitrile or dimethylformamide, in the presence of a basesuch as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine orthe like at a temperature of from -20° to 40° C. for from 0.5 to 5hours. The leaving group X is intermediate 13 can also be halogen. Thehalogen leaving group is established by treating 12 with a halogenatingagent such as φ₃ PCl₂, φ₃ PBr₂, (φO)₃ PBr₂, oxalyl chloride or the likein a solvent such as CH₂ Cl₂, CH₃ CN, THF, or the like in the presenceof a base such as diisopropylethylamine, triethylamine, or4-dimethylaminopyridine or the like. [φ= phenyl.]

The leaving group X can also be a phosphate. It is typically prepared bytreating 12 with diethyl chlorophosphate or the like in the presence ofa base such as diisopropylethylamine, triethylamine, or4-dimethylaminopyridine or the like.

The leaving group X can also be a carbonate. It is prepared by treating12 with a chloroformate such as methyl, benzyl, p-nitrobenzyl or thelike in the presence of a base such as diisopropylethylamine,triethylamine, or 4-dimethylaminopyridine or the like.

The leaving group X can also be an imino ester: ##STR4## It is preparedby treating 12 with an imidoyl chloride such as N-phenyltrimethylacetimido chloride in the presence of a base such asdiisopropylethylamine, triethylamine, or 4-dimethylaminopyridine or thelike.

The reaction 13→13 is accomplished by treating 13 in a solvent such asdioxane, dimethylformamide, dimethylsulfoxide, acetonitrile,hexamethylphosphoramide, or the like in the presence of an approximatelyequivalent to excess of the mercaptan reagent HSCH₂ CH₂ NHR⁴ wherein R⁴is hydrogen or a readily removable N-protecting group such asp-nitrobenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, formimidoyl,phenoxyacetyl, phenylacetyl, 2-methyl-2-(o-nitrophenoxy)propionic, ando-nitrophenoxyacetic, or the like in the presence of a base such assodium hydrogen carbonate, potassium carbonate, triethylamine,diisopropylethylamine, or the like at a temperature of from -40° to 25°C. for from 1 to 72 hours. The mercaptan reagent, HSCH₂ CH₂ NHR⁴, istypically prepared by treating aminoethylmercaptan in the presence ofthe desired acid chloride in the presence of a base such as sodiumbicarbonate, sodium hydroxide, or the like in a solvent such as aqueousdiethylether, aqueous dioxane, aqueous acetone, or the like at atemperature of from 0° to 25° C. for from 0.5 to 4 hours.

The final deblocking step 14→I is accomplished by conventionalprocedures such as hydrolysis or hydrogenation, or enzymatically.Typically 14 in a solvent such as dioxane-water-ethanol;tetrahydrofuran-aqueous dipotassium hydrogen phosphate-isopropanol;tetrahydrofuran-water-morpholinopropane-sulfonic acid (adjusted pH to7.0 by adding sodium hydroxide); or the like is treated under a hydrogenpressure of from 1 to 4 atmospheres in the presence of a hydrogenationcatalyst such as palladium on charcoal, palladium hydroxide, platinumoxide, or the like at a temperature of from 0° to 50° C. for from 0.5 to4 hours to provide I.

In the foregoing word description of the above schematic reactiondiagram for the total synthesis of thienamycin, it is to be understoodthat there is considerable latitude in selection of precise reactionparameters. Suggestion of this latitude and its breadth is generallyindicated by the enumeration of equivalent solvent systems, temperatureranges, protecting groups, and range of identities of involved reagents.Further, it is to be understood that the presentation of the syntheticscheme as comprising distinct steps in a given sequence is more in thenature of a descriptive convenience than as a necessary requirement; forone will recognize that the mechanically dissected scheme represents aunified scheme of synthesis and that certain steps, in actual practice,are capable of being merged, conducted simultaneously, or effected in areverse sequence without materially altering the progress of synthesis.

The following examples recite a precise scheme of total synthesis. It isbe be understood that the purpose of this recitation is to furtherillustrate the total synthesis and not to impose any limitation. Alltemperatures are in °C.

EXAMPLE 1 3-Benzylamino-2-pentenedioic acid diethyl ester (2) ##STR5##

Benzylamine (89.1 g, 0.83 moles) is added over 10 minutes to asuspension of 5A powdered molecular sieves (270 g) and diethyl1,3-acetonecarboxylate (160 g) (0.79 moles) in 350 ml toluene (externalcooling applied to control exotherm). The suspension is stirred at roomtemperature for 14-17 hours and then filtered to provide 2. The filtercake is washed with three portions of toluene. The combined filtratesmay be used as is in the subsequent ketene reaction.

EXAMPLE 2 2-Acetyl-3-benzylamino-2-pentenedioic acid diethyl ester (3)##STR6##

Ketene gas (generated by pyrolysis of acetone) is passed through thestirred solution of 2 (see Example 1, above) at 22° C. When startingmaterial 2 is completely consumed (followed by TLC-solvent system 1:1hexane/EtOAc), the solution is concentrated to give the product as a tansolid.

Yield=270.2 g (103%, purity by NMR ca 90%).

Recrystallization from ethanol affords the pure product 3 as colorlessneedles, mp 87°-8° C.

    ______________________________________                                        Elem. anal.           Calc.    Found                                          ______________________________________                                        C.sub.18 H.sub.23 NO.sub.5                                                               C           64.85%   64.90%                                                   H          6.95     7.06                                                      N          4.20     3.94                                           ______________________________________                                    

EXAMPLE 3 (2SR, 3RS)-2-[1(SR)-hydroxyethyl]-3-(benzylamino)pentanedioicacid diethyl ester 4 ##STR7##

A solution of the enamine 3 (83.3 g, 0.25 mmoles) in 400 ml HOAc (aceticacid) is chilled to ca. 10° C. and sodium cyanoborohydride (20.9 g, 0.33moles) is added as a solid portionwise over 15-30 minutes. The coolingbath is removed and the solution stirred at room temperature (22° C.)for 3.5 hours. The solution is concentrated in vacuo and the residueflushed with toluene to remove most of the acetic acid. The residue ispartitioned between 400 ml EtOAc (ethyl acetate) and 300 ml saturatedaqueous NaHCO₃. The organic layer is washed with another 300 ml portionof aqueous NaHCO₃. The combined aqueous layers are back extracted with200 ml EtOAc. The organic layers are dried (Na₂ SO₄) and concentrated invacuo to give 4 as a colorless gum, 100 g.

EXAMPLE 4Tetrahydro-2α-methyl-6-oxo-4β-benzylamino-2H-pyran-3α-carboxylic acidhydrochloride 5 ##STR8##

The crude amino alcohol 4 (110 g) is cautiously dissolved in 900 mlconcentrated aqueous HCl. The solution is heated to reflux and 80-100 mlof distillate is collected (discarded) during the first hour of reflux.After a 3 hr. reflux period the solution is cooled to 0° for 45 min andfiltered. The solid is washed with three portions of 40% EtOH inisopropanol and dried in vacuo to constant weight to yield 5: 24-30 g ofwhite crystalline solid; mp 160°-170° (dec).

    ______________________________________                                        Elem. Anal.              Calcd.  Found                                        ______________________________________                                        C.sub.14 H.sub.18 ClNO.sub.4.H.sub.2 O                                                         C       52.91   52.79                                                         H       6.34    6.41                                                          Cl      11.16   11.00                                                         N       4.41    4.51                                         ______________________________________                                    

EXAMPLE 4aTetrahydro-2α-methyl-6-oxo-4β-benzylamino-2H-pyran-3α-carboxylic acidethyl ester hydrochloride 5 ##STR9##

A similar batch of crude amino alcohol 4 (101.7 g) in 900 ml CH₂ Cl₂ istreated with HCl gas (subsurface introduction) for 1 hour. The saturatedsolution (or suspension) is stirred at room temperature for another 2hours. Ether (800 ml) is added to the suspension and cooled to 0° for 1hr. The solid is collected, washed with two cold portions of CH₂ Cl₂ anddried in vacuo to yield 5:

Yield: 26.6 g (35% from diethyl 1,3-acetonedicarboxylate) mp 181°-7°(dec).

    ______________________________________                                        Elem. Anal.            Calcd   Found                                          ______________________________________                                        C.sub.16 H.sub.22 ClNO.sub.4                                                                C        58.62   58.95                                                        H        6.77    6.79                                                         Cl       10.82   10.94                                                        N        4.27    4.69                                           ______________________________________                                    

EXAMPLE 5 (3SR,4RS)-1-(tert-butyldimethylsilyl)-3-[1(RS)-tert-butyldimethylsilyloxyethyl]-2-oxo-4-azetidineaceticacid benzyl ester 11 ##STR10##

Triethylamine (0.937 g, 9.28 mmole) in 3 ml DMF (sieve-dried) is addedto the β-lactam (1.056 g, 4.01 mmol) in 15 ml DMF at room temperature.The solution is chilled to 0° and tert-butyldimethylsilyl chloride (1.39g, 9.28 mmole) is added as a solid in 3 portions over 5 minutes. Thesuspension is aged at 0° for 15 minutes then at room temperature for 19hours. The orange-brown suspension is diluted with H₂ O and extractedwith EtOAc. The organic layer is washed with H₂ O, brine, dried andconcentrated to give the product 11 as a colorless gum (2.0 g) thatsolidifies on standing.

EXAMPLE 6 (3SR,4RS)-1-(tert-butyldimethylsilyl)-3-[1(RS)-tert-butyldimethylsilyloxyethyl]-2-oxo-4-azetidineaceticacid 12 ##STR11##

A suspension of the crude benzyl ester 11 (2.00 g, 4.01 mmole) and 1/2 g10% Pd/C in 40 ml. MeOH is pressurized (40 psi) with H₂ and shaken for75 minutes. The suspension is filtered and the filtrate is concentratedin vacuo to give the product 12 as a white solid, 1.60 g.

Analytical sample from EtOAc as white needles, m.p. 168°-9°

    ______________________________________                                        Calcd. for            Calculated                                                                              Found                                         ______________________________________                                        C.sub.19 H.sub.39 NO.sub.4 Si.sub.2                                                         C       56.81     56.95                                                       H       9.79      9.98                                                        N       3.49      3.45                                                        Si      13.98     did not                                                                       analyze                                                                       properly                                      ______________________________________                                    

EXAMPLE 7 (3SR,4RS)-1-(tert-butyldimethylsilyl)-3-[1(RS)-tert-butyldimethylsilyloxyethyl]-β,2-dioxo-4-azetidinebutanoicacid p-nitrobenzyl ester 13 ##STR12##

To a solution of the β-lactam 12 (1.46 g., 3.62 mmole) in 30 ml. CH₂ Cl₂at room temperature is added 1,1'-carbonyldiimidazole (0.64 g., 3.95mmole). After stirring for 30 minutes the solution is treated with2,2-dimethyl-1,3-dioxane-4,6-dione (0.78 g., 5.43 mmole) and4-dimethylaminopyridine (0.66 g., 5.43 mmole) and the solution aged atroom temperature for another 70 hours. The solution is washed with 1Naqueous HCl followed by H₂ O and then dried with Na₂ SO₄ andconcentrated. The residue is dissolved in 20 ml. MeCN, p-nitrobenzylalcohol (0.94 g., 6.15 mmole) is added, and the solution is heated toreflux for 1 hour. The reaction mixture is concentrated to a gummysolid. The pure product 13 is isolated by crystallization fromisopropanol; or by chromatography on silica gel (eluent, hexane-EtOAc,7/3).

Analytical sample from 1/1 hexane/Et₂ O, colorless needles, m.p.113.5°-115°.

    ______________________________________                                        Calcd. for             Calcd.  Found                                          ______________________________________                                        C.sub.28 H.sub.46 N.sub.2 O.sub.7 Si.sub.2                                                   C       58.09   58.31                                                         H       8.01    8.25                                                          N       4.84    4.76                                                          Si      9.70    did not                                                                       analyze                                                                       properly                                       ______________________________________                                    

EXAMPLE 8 (3SR,4RS)-3-(1(RS)-hydroxyethyl)-β,2-dioxo-4-azetidinebutanoic acidp-nitrobenzyl ester ##STR13##

Concentrated aqueous HCl (0.45 ml) is added to a suspension of the silylderivative (0.63 g., 1.09 mmole) in 30 ml. of 10% aqueous MeOH. Afterstirring at room temperature for 6 hours, the solution is concentratedalmost to dryness. The residue containing 14 is partitioned between H₂ Oand CH₂ Cl₂. The organic layer is dried (MgSO₄) and concentrated to acolorless gum, 0.40 g. The crude product is used as is in the next step.

Analytical sample from hexane/EtOAc, m.p. 97°-9°.

    ______________________________________                                        Calcd. for             Calcd.  Found                                          ______________________________________                                        C.sub.16 H.sub.18 N.sub.2 O.sub.7                                                         C          54.85   55.02                                                      H          5.18    5.38                                                       N          8.00    7.79                                           ______________________________________                                    

EXAMPLE 9 (3SR,4RS)-α-diazo-3-[1(RS)-hydroxyethyl]-β,2-dioxo-4-azetidinebutanoic acidp-nitrobenzyl ester 15 ##STR14##

A solution of the crude β-keto ester 14 (0.83 g., 2.37 mmole) andp-toluenesulfonyl azide (0.56 g, 2.85 mmole) in 10 ml EtOAc at roomtemperature is treated with a solution of NEt₃ (0.31 g., 3.08 mmole) in2 ml. EtOAc. The resulting suspension is stirred for 1 hr., chilled to0° and filtered. The product 15 (0.77 g) is analytically pure, m.p.160.5°-2° (dec.).

    ______________________________________                                        Elem. Anal.            Calcd.  Found                                          ______________________________________                                        C.sub.16 H.sub.16 N.sub.4 O.sub.7                                                         C          51.06   51.04                                                      H          4.29    4.22                                                       N          14.89   14.76                                          ______________________________________                                    

EXAMPLE 10(5RS,6SR)-6-[(RS)-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylicacid p-nitrobenzyl ester ##STR15##

A stirred suspension of the diazo compound 15 (500 mg, 1.33 mmole) andrhodium diacetate (15 mg) in dry toluene (35 ml) is heated to 80°-5° for2.5 hours. After filtration of the catalyst, the solution isconcentrated in vacuo to give the product as a white solid, mp 92°-8°.

EXAMPLE 11(5RS,6SR)-6-[(RS)-1-hydroxyethyl]-3-[2-(p-nitrobenzyloxycarbonyl)aminoethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid p-nitrobenzyl ester ##STR16## PROCEDURE A: TrifluoromethylsulfonylActivation

To a stirred suspension of the bicyclic ketone 16 (100 mg, 0.287 mmole)in dry methylene chloride (1 ml) is added dropwise a solution ofdiisopropylethylamine (62 mg, 0.481 mmole) in dry CH₂ Cl₂ (0.4 ml) at 0°C. under a nitrogen atmosphere. The resulting mixture is aged for 15min. then trifluoromethanesulfonic anhydride (90 mg, 0.319 mmole) isadded to give a clear solution. To the mixture is added a solution ofdiisopropylethylamine (250 mg, 1.94 mmole) in CH₂ Cl₂ (0.3 ml) followedby N-p-nitroenzyloxycarbonylcysteamine (77 mg, 0.30 mmole) as a solid at0° C. The mixture is stirred for 30 min during which time the productcrystallizes as a colorless solid. The solid is collected by filtrationand washed with CH₂ Cl₂. An additional crop of product is obtained bywashing the filtrate with dilute aqueous NaHCO₃. The organic layer isdried with Na₂ SO₄ and concentrated in vacuo. The residue iscrystallized from EtOAC. The combined yield is 108 mg (64%) of product17.

PROCEDURE B: Tosylate Activation

To a suspension of the bicyclic ketone 16 (50 mg, 0.144 mmole) inacetonitrile (3 ml) is added dropwise a solution ofdiisopropylethylamine (22 mg, 0.171 mmole) in 1 ml CH₃ CN at -5° C.under a nitrogen atmosphere. After aging at this temperature for 10 min,a solution of p-toluene sulfonic anhydride (51 mg, 0.156 mmole) in 1 mlCH₃ CN is added. The resulting mixture is stirred for 2 hr. at 0° C. Thesolution is concentrated in vacuo to a volume of approximately 1 ml andthen 3 ml of dry N,N-dimethylformamide (DMF) is added and the remainingCH₃ CN removed in vacuo. To the DMF solution at -5° C. is added asolution of diisopropylethylamine (40 mg, 0.31 mmole) in 0.5 ml DMF andthe resulting mixture stored in a refrigerator for 70 hrs. The solutionis diluted with brine and extracted with five portions of CH₂ Cl₂. Thecombined extracts are washed with brine, dried over Na₄ SO₄, andconcentrated in vacuo. The residue is crystallized from anethylacetate-ether mixture to give the product 17 as a colorless solid,68 mg (81%).

PROCEDURE C: Phosphate activation

To a suspension of the bicyclic ketone 16 (100 mg, 0.29 mmole) in CH₃ CN(1 ml) is added dropwise a solution of diisopropylethylamine (37 mg,0.29 mmole) in 0.4 ml CH₃ CN at 0° under a nitrogen atmosphere. Theresulting mixture is stirred for 15 min then a solution of diphenylchlorophosphate (77 mg, 0.29 mmole) in 0.4 ml CH₃ CN is added. Themixture is stirred for 15 min at 0° and then 15 min at room temperature.The mixture is again cooled to 0° and a solution ofdiisopropylethylamine (38.7 mg, 0.30 mmole) in 0.4 ml CH₃ CN is addedfollowed by N-p-nitrobenzyloxycarbonylcysteamine (77 mg, 0.30 mmole).The reaction mixture is stored overnight in a freezer, diluted withEtOAC, and filtered to give the product 17 as a colorless solid, 118 mg(70%).

EXAMPLE 12 Thienamycin ##STR17##

A mixture of the protected thienamycin 17 (4.9 mg, 8.632×10⁻⁶ mole) andplatinum oxide (3.4 mg) in tetrahydrofuran (2 ml), water (1 ml) and 0.5Mmorpholinopropane sulfonic acid (adjusted to pH 7.0 by adding sodiumhydroxide) (0.5 ml) is hydrogenated at 40 psi on a Parr shaker for 60minutes. The suspension is filtered to remove catalyst and the catalystis washed with water (2×20 ml). The filtrate is washed with EtOAC (2×15ml). The aqueous layer is diluted to 50 ml and assayed for thienamycin.

UV λ_(max) =298 mm.

HPLC assay 81.4% yield, retention time=298 sec., natural thienamycin 298sec.

EXAMPLE 13 Tetrahydro-2α-methyl-6-oxo-4β-amino-2H-pyran-3α-carboxylicacid hydrochloride ##STR18##

A suspension of the benzyl lactone (5.00 g 0.0167 moles) and 1.0 g of10% Pd/C in 200 ml acetic acid is pressurized to 1500 psi with hydrogen.The mixture is agitated at room temperature for 3 days, vented, andfiltered. The recovered catalyst is washed with 2 portions (ca. 15 ml)of HOAc. The combined filtrates are concentrated in vacuo.

Yield=4.00 g (114%) of white, foamy gum containing residual acetic acid.

Analytical sample prepared by crystallization from an aceticacid-acetonitrile-toluene mixture, mp 160°-5° (dec).

    ______________________________________                                        Elem. Anal.            Calcd.  Found                                          ______________________________________                                        C.sub.7 H.sub.12 ClNO.sub.4                                                                 C        40.10   40.05                                                        H        5.77    5.90                                                         N        6.68    6.93                                                         Cl       16.91   16.97                                          ______________________________________                                    

EXAMPLE 14 (2SR, 3RS)-3-amino-2[1(SR)-hyroxyethyl]pentanedioic acid5-benzyl ester hydrochloride ##STR19##

The crude amino acid (2.90 g, ca. 12.1 mmole) is dissolved in 40 ml. ofbenzyl alcohol and heated to 70°-75° for 1 day. The solution is dilutedwith toluene (70 ml) and the product extracted with 2 portions (20 mleach) H₂ O. The combined aqueous layers are washed with toluene (40 ml)and concentrated in vacuo, to give 3.10 g of crude product as a foamygum.

This crude material can be used as is for the next step. Alternatively,pure, crystalline material can be obtained as follows:

Acetonitrile (40 ml) is added to 2.61 g of the crude amino acid and themixture is stirred until the gum is all transformed to white solid (1-2hrs.). The suspension is cooled to 0°, filtered, and washed withisopropyl alcohol.

Yield=1.90 g white powder (59% yield from benzyl lactone).

    ______________________________________                                        Elem. Anal.            Calcd.  Found                                          ______________________________________                                        C.sub.14 H.sub.20 ClNO.sub.5                                                                C        52.91   52.80                                                        H        6.34    6.54                                                         Cl       11.16   11.00                                                        N        4.41    4.33                                           ______________________________________                                    

The combined filtrates containing additional product and unreactedlactone can be concentrated and recycled.

EXAMPLE 15 (3SR, 4RS)-3-[1(SR)-hydroxyethyl]-2-oxo-4-azetidineaceticacid benzyl ester ##STR20##

Triethylamine (5.24 g, 51.9 mmol) is added to a suspension of the pureacid amino acid (16.00 g, 50.3 mmol) in 200 ml acetonitrile at roomtemperature. The mixture is aged for 5 minutes, thenN,N'-dicyclohexylcarbodiimide (10.88 g, 52.8 mmol) is added as a solid.After aging at room temperature for 10 minutes, the suspension is heatedto 60° for 3 hours and then concentrated. The residue is slurried incold EtOAc and filtered to remove the urea. The filtrate is washedsuccessively with 2N HCl, H₂ O, satd. NaHCO₃ (these extracts are allback-extracted with EtOAc), and brine, dried (MgSO₄) and concentrated.The crude product (13.2 g) is pure enough (the only impurity is about 5%of the cyclohexylurea) to use in the subsequent steps, however,analytically pure material may be prepared either by crystallisationfrom diethyl ether or chromatography on silica gel (eluent, 20%hexane-EtOAc), mp 67.5°-68.5°.

    ______________________________________                                        Elem. Anal.            Calcd   Found                                          ______________________________________                                                    C          63.86   63.86                                                      H          6.51    6.56                                                       N          5.32    5.43                                           ______________________________________                                    

EXAMPLE 16 (3SR, 4RS)-3-acetyl-2-oxo-4-azetidineacetic acid benzyl ester##STR21##

The alcohol (1.07 g, 4.07 mmole) in 20 ml acetone is cooled to 0° andtreated with Jones reagent (prepared according to Eisenbraun, OrganicSyntheses, Coll. Vol. V, pg 310) until the orange color of the reagentpersists. The mixture is aged 15 min. and the excess reagent destroyedby addition of 0.2 ml isopropanol. The mixture is concentrated and theresidue partitioned between EtOAc and dilute aqueous HCl. The organiclayer is washed with brine, dried with Na₂ SO₄ and concentrated to givethe product as a pale yellow solid (0.96 g).

EXAMPLE 17 (3SR, 4RS)-3-[1(RS)-hydroxyethyl]-2-oxo-4-azetidineaceticacid and (3SR, 4RS)-3-[1(SR)-hydroxyethyl]-2-oxo-4-azetidineacetic acidbenzyl ester ##STR22##

To a solution of the ketone (249 mg, 0.95 mmole) in 3 ml HOAc at roomtemperature is added sodium cyanoborohydride (60 mg, 0.95 mmole) as asolid. The solution is aged for 1 hour and concentrated in vacuo. Theresidue is partitioned between EtOAc and saturated aqueous NaHCO₃ (2portions). The organic layer is dried (Na₂ SO₄) and concentrated to agum. The crude product containing both isomeric alcohols is crystallizedfrom EtOAc/hexane to give the RSR/SRS alcohol as colorless needles.

The mother liquor can be re-oxidized and recycled.

CROSS REFERENCE TO RELATED APPLICATIONS

The following concurrently filed, commonly assigned U.S. patentapplications are similarly directed to totally synthetic schemes for thepreparation of thienamycin and in that respect complement the disclosureof the present application; consequently, these applications areincorporated herein by reference.

1. U.S. patent application Ser. No. 112,058 filed Nov. 4, 1980 [Merck &Co., Inc., of Thomas M. H. Liu, et al.], abandoned

2. U.S. patent application Ser. No. 112,020 filed Nov. 4, 1980 [Merck &Co., Inc., of George Gal, et al.] abandoned

3. U.S. patent application Ser. No. 112,021 filed Nov. 4, 1980 [Merck &Co., Inc., of Thomas M. H. Liu, et al.], abandoned

4. U.S. patent application Ser. No. 112,057 filed Nov. 4, 1980 [Merck &Co., Inc., of David G. Mellillo, et al.], U.S. Pat. No. 4,269,772.

5. U.S. patent application Ser. No. 112,022 filed Nov. 4, 1980 [Merck &Co., Inc., of Thomas M. H. Liu, et al.], U.S. Pat. No. 4,282,148.

What is claimed is:
 1. A compound having the structural formula##STR23## wherein R¹ is hydrogen or a removable protecting groupselected from benzyl, β,β,β-trichloroethyl, methyl, ethyl, phenyl andt-butyl.